Iontophoretic Transmucosal Delivery Of Unfractionated And Low Molecular Weight Heparins

In order to improve the bioavailability of macromolecule drugs such as peptide and protein through mucosa, the iontophoresis and penetration enhancer were used with LMWH and UFH as model drugs. Sodium heparin(UFH as well as LMWH) can ionize in water, and has to be administered by injection. The molecular weight of UFH is about 14000 daltons (range 3000～30000 daltons),and the LMWH?s is about 5000 daltons (range 3000～8000 daltons).The Activated Partial Thromboplastin Time(APTT) method was used to determinate LMWH and UFH in various solution through various mucosa and in the animal plasma after administration. The coefficients correlation of the standard curve were 0.9951 and 0.9967 for LMWH and UFH, and the pH of the solution, mucosa homogenate and electrical field had no interference for the method.The order of permeability coefficient of LMWH and UFH for different mucosa was chicken crop>dogs? oral cavity>rats? intestine. The enhancer(5% Labrasol) increased the penetration of LMWH and UFH through mucosa both in vitro and in vivo.We proved that the iontophoresis can significantly improve the permeability of LMWH and UFH using not only the DC but also the PC in the same electrical intensity. The pulsed current with [on/off] ratio 1:1 and cycle of 60 times per minute is better than other electricity pattern in iontophoretic mucosal permeation. The ER of 2000 IU/ml LMWH solution and 4000 IU/ml UFH solution permeated rats? rectal mucosa were 37.45 and 38.66 respectively.The LMWH and UFH films prepared with Carbopol and Alginate Sodium were for oral cavity delivery, the polyoxyethylene (PEO) gum-solution was prepared for rectal administration. It was found that the bioavailability of LMWH PEO gum-solution administered in rabbits? rectum using iontophoresis(0.33mA/cm2 DC) was 25% of the sc administration, which was 8 times higher than without iontophoresis.The oral bioavailability of LMWH and UFH solution administered in rats were 7% and below 1% respectively. If the solution contained 5% Labrasol, the bioavailability of LMWH was increased to 14%, but that of UFH was still below 1%.With 0.45mA/cm2 PC iontophoresis, the bioavailabilities of LMWH and UFH films iontophoresis administered in rats? oral cavity were approximately 20% and 6% respectively compared with sc.Under the same electricity, the bioavaibilities of LMWH and UFH PEO gum-solution administered from rat rectum was 35% and 16% respectively.It suggested that the rectal iontophoretic delivery system is a useful vehicle to improve the absorption of macromolecuar drugs, and we believe it would be developed as combination products in the near future.